There is no reparative treatment for neural retina destroyed by trauma or degenerative diseases. To advance stem cell transplantation and regenerative therapies as means of retinal repair, it is imperative to understand the exchange of genetic material between stem/progenitor cells and retinal cells (2, 3). Importantly, embryonic stem (ES), neurons and glia package genetic material for transfer to surrounding cells in secretory microvesicles (6, 11, 16, 18, 19, and 28). Retinal neural microvesicles are predicted to direct stem/progenitor cell fate, while stem cell secreted microvesicles are predicted to promote neuroprotection and possibly transdifferentiation toward regeneration in injured retinal cells. The goals of the proposed research are to identify the molecular mechanisms of intercellular microvesicle signaling between mouse ES, retinal progenitor cells (RPCs), adult retinal neural and glia cells in normal and disease states and define the capabilities of this signaling to influence cell fate and retinal regeneration. To accomplish this effort the specific aims of the proposed study include: 1) Characterization of microRNA, mRNA and protein contained in mouse ES, RPC, retinal neural and glial cell microvesicles, 2) Evaluation of intercellular transfer of microRNA, mRNA, and protein in microvesicles between ES, RPC, retinal neural and glial cells and 3) Characterization of microvesicle mediated cellular changes in an in vitro retinal disease model at the level of microRNA, mRNA, protein and physiology. It is predicted that 1) MVs will contain a subset of microRNA, mRNA and protein similar to those found in cells of origin, 2) Incubation of ES, RPC, retinal neurons and glia with microvesicles collected from other cell types will result in microvesicle binding to recipient cell membranes and intracellular deposition of genetic material and 3) ES and RPC microvesicles will confer trophic protection and self- renewal/transdifferentiation potential to retinal neurons and glia, respectively. Also, retinal neural and glial microvesicles will confer neural and glial programming and fate determination to ES and RPCs (6, 11, 16, 18, 19, and 28). A long-term goal of this study is the development of MV signaling based therapeutics to enhance stem cell transplantation and retinal regeneration. Findings from this study will be developed in future studies via testing ocular injections of microvesicles for neural protective and regenerative properties in vivo retinal disease and trauma models. An additional future study will analyze the encapsulation of microvesicles in biodegradable polymer microspheres for long-term ocular release to treat retinal tissue damaged by disease or trauma (34). This is a newly emerging area of study with potentially significant implications for transplanted stem cell fate, functional regeneration and repair of damaged retina and other regions of the central nervous system. PUBLIC HEALTH RELEVANCE: Retinal stem cell delivery and retinal regeneration are promising therapeutic strategies to repair damaged retina and restore lost vision. To improve the success of these strategies, retinal stem cells must become neurons prior to transplantation and damaged retina must be given signals to regenerate. This study will describe a novel mechanism with the potential to elucidate these processes and contribute to retinal repair.